Lipophilicity is an important molecular property in drug discovery. The exact knowledge of drug lipophilicity is useful for correlation with pharmaceutical processes such as membrane permeation, solubility, volume of distribution, metabolic stability and protein binding. Lipophilicity is expressed either by log P (octanol-water Partition coefficient for neutral species) or log D (octanol-water Distribution coefficient for charged molecules).
Usually, the lipophilicity is determined by the conventional shake-flask method (M. M. Abraham, H. S. Chadha, J. P. Dixon, and A. J. Leo. Hydrogen bonding. Part 9. The partition of solutes between water and various alcohols. Phys. Org. Chem. 7:712-716 (1994). When performed manually, this method is very time consuming (only 2-5 compounds per day). However, the number of compounds produced in drug discovery increased dramatically due to rapid analogue synthesis and combinatorial chemistry. This situation requests for a fast and efficient method for determining the lipophilicity of compounds.
Further, the methods of the prior art do not work with low soluble compounds. Since 2002 about 35% of the log D measurements were failed due to the precipitation of compounds in the reference solution or low sample concentrations in the aqueous phase (source: RODIN and SPC database, 2004). On the other hand, there is a need for high throughput measurements of log D>4, especially for drug targets where high lipophilicity is required.
Therefore, there is a requirement for a method which is fast and which allows the determination of lipophilicity of low soluble compounds.